Co-chaperones modulate the activity of chaperones, primarily heat shock proteins (HSPs), either directly or indirectly through the recruitment of other proteins (Walsh et al., 2004, EMBO Rep 5, 567-571). Although the regulation and role of chaperones have been extensively studied, little is known about the function of the large number of identified co-chaperones. The DnaJ family of co-chaperones is the largest and the most diverse with 49 identified members in humans. It is characterized by the presence of the highly conserved 70 aa J-domain containing a His-Pro-Asp motif that binds to the ATPase domain of HSP70 family members and promotes their ATPase activity (Walsh et al., 2004, EMBO Rep 5, 567-571; Mitra et al., 2009, Clin Exp Metastasis 26, 559-567; Sterrenberg et al., 2011, Cancer Lett 312, 129-142). The members of this family have been classified in three subfamilies according to the presence and nature of sequences other than the J-domain (DnaJA, DnaJB and DnaJC subfamilies) (Kampinga et al., 2009, Cell Stress Chaperones 14, 105-111). The DnaJA subfamily contains a Gly/Phe (G/F) rich region and a Cys repeat region, while the DnaJB subfamily contains the G/F region but lacks the Cys-repeat region. DnaJC subfamily members are highly diverse. They lack both the G/F and Cys-repeat regions, while their J domain can be located at any position in the protein. However, most DnaJC members have less characterized non-classical domains that seem to provide specificity for partner binding and function.
DnaJ co-chaperones can interact with proteins other than HSPs in a DnaJ-domain independent manner to mediate specific functions (Sterrenberg et al., 2011 Cancer Lett 312, 129-142). However, only a few targets have been identified. Within the mitochondria, the DNA polymerase gamma (Polga) has been shown to interact with Tidl (Hayashi et al., 2006 Nat Med 12, 128-132), and more recent studies have also identified p53 as another potential target (Ahn et al., 2010 Oncogene 29, 1155-1166). DnaJA1 has also been recently found to interact with Adenosin Induced Deaminase (AID) in B cells and modulate its activity during class switching recombination (Orthwein et al., EMBO J 2011 Nov. 15; 31(3):679-91.). The role of DnaJ co-chaperones in cancer is a functional aspect of these proteins that has begun to be investigated, although primarily in cell lines (Mitra et al., 2009, Clin Exp Metastasis 26, 559-567). In addition, only a few orthologs of human DnaJ proteins have been identified in mouse (e.g., DnaJC10/ERdj5, DnaJB6/Mrj and DnaJA3/Tid1, DnaJA1/DjA1) (Terada et al., 2005, EMBO J 24, 611-622; Hosoda et al., 2010, Biochem J 425, 117-125; Lo et al., 2004, Mol Cell Biol 24, 2226-2236; Hunter et al., 1999, Development 126, 1247-1258).
The absence of known domains and the presence of poorly characterized non-classical domains have made it difficult to characterize the functions of most DnaJC family members. As a consequence, and despite the large number of DnaJ co-chaperones identified in humans, their function in normal and disease conditions remain mostly unknown.